Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases

Zhou, Danlei; Rudnicki, Michael; Chua, Gilbert T.; Lawrance, Simon K.; Zhou, Bi; Drew, Joanne; Barbar-Smiley, Fatima; Armstrong, Taylor; Hilt, Miranda E.; Birmingham, Daniel J.; Passler, Werner; Auletta, Jeffery J.; Bowden, Sasigarn A; Hoffman, Robert P.; Wu, Yee Ling; Jarjour, Wael; Mok, Chi Chiu; Ardoin, Stacy P.; Lau, Yu Lung; Yu, C. Yung

doi:10.3389/fimmu.2021.739430

Cited by 17 publications

(17 citation statements)

References 60 publications

(124 reference statements)

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“…This includes, for instance, the C4A and C4B isotypes of complement factor 4, which cannot be distinguished by affinitybased platforms (Supplementary Table 5). Their sequences differ in less than one percent, but this greatly affects their binding affinity towards their molecular targets 40 . Of the remaining pQTLs, 61% were replicated in at least five studies (Extended Data Fig.…”

Section: Novel Pqtls Link Proteins To Gwas Resultsmentioning

confidence: 99%

Plasma Proteome Variation and its Genetic Determinants in Children and Adolescents

Niu

Stinson

Holm

et al. 2023

Preprint

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The levels of specific proteins in human blood are the most commonly used indicators of potential health-related problems. Understanding the genetic and other determinants of the human plasma proteome can aid in biomarker research and drug development. Diverse factors including genetics, age, sex, body mass index (BMI), growth and development including puberty can affect the circulating levels of proteins. Affinity-based proteomics can infer the relationship between blood protein levels and these factors at a large scale. Compared to these methods, mass spectrometry (MS)-based proteomics provides much higher specificity of identification and quantification, but existing studies are limited by small sample sizes or low numbers of quantified proteins. Here we aim to elucidate to which extent genomic variation affects plasma protein levels across diverse age ranges and cohort characteristics. Employing a streamlined and highly quantitative MS-based plasma proteomics workflow, we measured the plasma proteome of 2,147 children and adolescents. Levels of 90% of these proteins were significantly associated with age, sex, BMI or genetics. More than 1,000 protein quantitative trait loci (pQTLs) - a third of which were novel - regulated protein levels between a few percent and up to 30-fold. These replicated excellently in an independent cohort of 558 adults, with highly concordant effect sizes (Pearson r > 0.97). We developed a framework to eliminate artefactual pQTLs due to protein-altering variants, paving the way for large-scale interrogation of pQTLs using MS-based proteomics. Our data reveal unexpectedly extensive genetic impacts on plasma protein levels, consistent from childhood into adulthood. These findings have implications for biomarker research and drug development.

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Section: Novel Pqtls Link Proteins To Gwas Resultsmentioning

confidence: 99%

Plasma Proteome Variation and its Genetic Determinants in Children and Adolescents

Niu

Stinson

Holm

et al. 2023

Preprint

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“…We postulate that activated C4A and C4B proteins interfere and balance each other’s effects physiologically to achieve optimum defence against infections and autoimmunity and mitigate collateral damages due to complement-mediated injuries of self-tissue. C4A deficiency, which is also indicated by low copy numbers of C4T or C4L, and higher proportion of C4B among total C4 ( C4B/C4T ), would disturb such dynamic equilibrium and skew the immune response towards inflammation and autoimmunity with generation of autoantibodies 25 32…”

Section: Discussionmentioning

confidence: 99%

“…C4A deficiency, which is also indicated by low copy numbers of C4T or C4L, and higher proportion of C4B among total C4 ( C4B/C4T ), would disturb such dynamic equilibrium and skew the immune response towards inflammation and autoimmunity with generation of autoantibodies. 25 32 …”

Section: Discussionmentioning

confidence: 99%

“…Complement C4 plays essential roles as an anchor protein in the activation of the classical and the mannan-binding lectin pathways for the humoral immunity (figure 1) to defend against infection 21 22. There are four layers of genetic complexity for human C4, which include (1) multiallelic gene copy number (GCN) variations with 2–10 copies of C4 genes present in a diploid genome among different individuals23–25; (2) gene size dichotomy with a long gene and a short gene depending on the integration of the 6.4 kb endogenous retrovirus HERV-K(C4) into intron 9 of long genes26 27; (3) each C4 gene either codes for an a cidic C4A or a b asic C4B protein, which differ by four specific amino acid residues between positions 1120 and 1125 coded by exon 26: PC PV LD for C4A and LS PV IH for C4B28 29 and (4) both C4A and C4B proteins are polymorphic with differential electrophoretic, serological and functional reactivities (figure 1). 25 28 30 Isotype deficiency of C4A has been shown to be strongly associated with increased susceptibility of lupus in multiple racial groups23 24 31 and in an animal model 32…”

Section: Introductionmentioning

confidence: 99%

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Low copy numbers of complementC4andC4Adeficiency are risk factors for myositis, its subgroups and autoantibodies

et al. 2022

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BackgroundIdiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown.MethodsWe elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion.ResultsThe large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28–2.91), p=5.0×10−53 for C4T, and 2.82 (2.48–3.21), p=7.0×10−57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44–84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies.ConclusionsC4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.

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“…C4B was an opsonin that covalently binds complement-activating targets ( Mayilyan et al, 2008 ). Recent studies have reported that diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune diseases ( Zhou et al, 2021 ). Our results demonstrated that the expression of C4B was also significantly elevated in the urine of active SLE, and was positively correlated with disease activity.…”

Section: Discussionmentioning

confidence: 99%

Significance of urine complement proteins in monitoring lupus activity

Zhao

Jiang

Wang

et al. 2022

PeerJ

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Objectives Complement activation is a critical feature in the development of systemic lupus erythematosus (SLE). Whether there are changes of complement components in the urine of SLE has not been reported. The aim of the study was to evaluate the complement-related proteins in the urine of SLE, verify differentially expressed proteins(DEPs) in the active phase of SLE, further explore their clinical application value. Methods First, we used bioinformatics and functional enrichment to screen and identify the urine protein profile of SLE patients. Then, analyzed and verified the proteins related to the complement pathway by western-blot and Parallel Reaction Monitoring (PRM) technology. Further evaluated the relationship between urinary DEPs related to complement pathway and disease activity. Results A total of 14 complement pathway-related proteins were screened for differences in expression between the active group and the stable group, eight of these DEPs were up-regulated and six were down-regulated. These DEPs may play a key role in SLE disease activity. We used PRM technology to verify the eight up-regulated proteins, and found that four of these complement proteins, namely C9, C8A, C4B, and C8G, were significantly increased in active group. Furthermore, these four DEPs were highly correlated with disease activity. In the urine of SLE patients, AUCs of 0.750, 0.840, 0.757 and 0.736 were achieved with C9, C8A, C4B, and C8G, respectively. Conclusions Complement-related DEPs in urine have a certain correlation with SLE disease activity. Urine C9, C8A, C4B and C8G present promising non-invasive biomarkers for monitoring lupus activity.

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Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases

Cited by 17 publications

References 60 publications

Plasma Proteome Variation and its Genetic Determinants in Children and Adolescents

Plasma Proteome Variation and its Genetic Determinants in Children and Adolescents

Low copy numbers of complementC4andC4Adeficiency are risk factors for myositis, its subgroups and autoantibodies

Significance of urine complement proteins in monitoring lupus activity

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